tbuckley/cabot-search huggingface dataset:
Rare variants in the sodium-dependent phosphate transporter gene SLC34A3 explain missing heritability of urinary stone disease
Authors: Omid Sadeghi-Alavijeh, Melanie M.Y. Chan, Shabbir H. Moochhala, Sarah Howles, Daniel P. Gale, Detlef Böckenhauer, John C. Ambrose, Prabhu Arumugam, Roel Bevers, Marta Bleda, Freya Boardman-Pretty, Christopher R. Boustred, Helen Brittain, Mark J. Caulfield, Georgia C. Chan, Greg Elgar, Tom Fowler, Adam Giess, Angela Hamblin, Shirley Henderson, Tim J.P. Hubbard, Rob Jackson, Louise J. Jones, Dalia Kasperaviciute, Melis Kayikci, Athanasios Kousathanas, Lea Lahnstein, Sarah E.A. Leigh, Ivonne U.S. Leong, Javier F. Lopez, Fiona Maleady-Crowe, Meriel McEntagart, Federico Minneci, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C. Need, Peter O’Donovan, Chris A. Odhams, Christine Patch, Mariana Buongermino Pereira, Daniel PerezGil, John Pullinger, Tahrima Rahim, Augusto Rendon, Tim Rogers, Kevin Savage, Kushmita Sawant, Richard H. Scott, Afshan Siddiq, Alexander Sieghart, Samuel C. Smith, Alona Sosinsky, Alexander Stuckey, Mélanie Tanguy, Ana Lisa Taylor Tavares, Ellen R.A. Thomas, Simon R. Thompson, Arianna Tucci, Matthew J. Welland, Eleanor Williams, Katarzyna Witkowska, Suzanne M. Wood
Journal: Kidney International (2023)

Urinary stone disease (USD) is a major health burden affecting over 10% of the United Kingdom population. While stone disease is associated with lifestyle, genetic factors also strongly contribute. Common genetic variants at multiple loci from genome-wide association studies account for 5% of the estimated 45% heritability of the disorder. Here, we investigated the extent to which rare genetic variation contributes to the unexplained heritability of USD. Among participants of the United Kingdom 100,000-genome project, 374 unrelated individuals were identified and assigned diagnostic codes indicative of USD. Whole genome gene-based rare variant testing and polygenic risk scoring against a control population of 24,930 ancestry-matched controls was performed. We observed (and replicated in an independent dataset) exome-wide significant enrichment of monoallelic rare, predicted damaging variants in the SLC34A3 gene for a sodium-dependent phosphate transporter that were present in 5% cases compared with 1.6% of controls. This gene was previously associated with autosomal recessive disease. The effect on USD risk of a qualifying SLC34A3 variants was greater than that of a standard deviation increase in polygenic risk derived from GWAS. Addition of the rare qualifying variants in SLC34A3 to a linear model including polygenic score increased the liability-adjusted heritability from 5.1% to 14.2% in the discovery cohort. We conclude that rare variants in SLC34A3 represent an important genetic risk factor for USD, with effect size intermediate between the fully penetrant rare variants linked with Mendelian disorders and common variants associated with USD. Thus, our findings explain some of the heritability unexplained by prior common variant genome-wide association studies.
The power of autonomy and resilience in healthcare delivery
Authors: Russell Mannion, Mark Exworthy, Siri Wiig, Jeffrey Braithwaite
Journal: BMJ (2023)

The power of autonomy and resilience in healthcare deliveryRussell Mannion and colleagues argue healthcare systems should learn from the good examples witnessed during the pandemic to enhance provider autonomy and resilience• Leaders have a crucial role in enhanc- ing workforce resilience by building competencies, balancing workloads, and fostering sound relations• Slack, the accumulated excess resources that are not immediately deployed to the work at hand, is at the heart of a resilient system on 18 August
Neurodevelopment of Children Exposed In Utero to Phenytoin and Carbamazepine Monotherapy
Authors: Dennis Scolnik
Journal: JAMA (1994)

<h3>Objective.</h3> —To compare pregnancy outcome prospectively after phenytoin and carbamazepine monotherapy with outcome in matched mother-child pairs exposed to nonteratogens to evaluate the relative fetal safety of these drugs. <h3>Design.</h3> —A prospective, controlled, and blinded observational study. <h3>Patients.</h3> —Thirty-six mother-child pairs exposed to carbamazepine monotherapy and 34 pairs exposed to phenytoin monotherapy, all prospectively studied, were compared with mother-child pairs exposed to nonteratogens. The controls were matched for maternal age, time of consultation, obstetric history, and socioeconomic status. <h3>Main Outcome Measure.</h3> —The primary end point of interest was the children's global IQ measured by either the Bayley or the McCarthy scale according to their ages. <h3>Setting.</h3> —A teratology consultation program and two neurology services in Toronto, Ontario. <h3>Results.</h3> — Children exposed to phenytoin in utero had a mean (±SD) global IQ 10 points lower (95% confidence interval, 4.9 to 15.8 points) than their matched controls (113.4±13.1 and 103.1±25.1;<i>P</i>=.038). The Reynell language development scores followed a similar trend, with children exposed to phenytoin scoring significantly lower than their controls. Phenytoin-exposed children had a global IQ of 84 or less significantly more often than the control group (<i>P</i>&lt;.01). Children exposed in utero to carbamazepine did not differ from their controls on any of the neurobehavioral tests. <h3>Conclusions.</h3> —Our study suggests a clinically important negative effect of phenytoin on neurobehavioral development, independent of maternal or environmental factors, causing a substantial number of children to achieve a lower score than expected on cognitive tests. No similar effects could be shown after gestational use of carbamazepine. (<i>JAMA</i>1994;271:767-770)
Glycome dynamics in T and B cell development: basic immunological mechanisms and clinical applications
Authors: Manuel M. Vicente, Eduarda Leite-Gomes, Salomé S. Pinho
Journal: Trends in Immunology (2023)

Glycans cover the surfaces of all mammalian cells through a process called glycosylation. Nearly all proteins and receptors that integrate the intricate series of co-stimulatory/inhibitory pathways of the immune system are glycosylated. Growing evidence indicates that the development of the immune system at the origins of T and B cell development is tightly regulated by glycosylation. In this opinion, we hypothesize that the glycome composition of developing T and B cells is developmentally regulated. We discuss how glycans play fundamental roles in lymphocyte development and how glycans early define T and B cell functionality in multiple aspects of adaptive immunity. These advances can provide opportunities for the discovery of novel disease factors and more effective candidate treatments for various conditions.
Diabetes detection in women with gestational diabetes and polycystic ovarian syndrome
Authors: Fahmy Hanna, Pensee Wu, Adrian Heald, Anthony Fryer
Journal: BMJ (2023)

Gestational diabetes mellitus (GDM) and polycystic ovarian syndrome (PCOS) represent two of the highest risk factors for development of type 2 diabetes mellitus in young women. As these increasingly common conditions generally affect younger women, early detection of dysglycemia is key if preventative measures are to be effective. While international guidance recommends screening for type 2 diabetes, current screening strategies suffer from significant challenges.First, guidance lacks consensus in defining which tests to use and frequency of monitoring, thereby sending mixed messages to healthcare professionals.Second, conformity to guidance is poor, with only a minority of women having tests at the recommended frequency (where specified). Approaches to improve conformity have focused on healthcare related factors (largely technology driven reminder systems), but patient factors such as convenience and clear messaging around risk have been neglected.Third, and most critically, current screening strategies are too generic and rely on tests that become abnormal far too late in the trajectory towards dysglycemia to offer opportunities for effective preventative measures. Risk factors show wide interindividual variation, and insulin sensitivity and β cell function are often abnormal during pre-diabetes stage, well before frank diabetes.New, consistent, targeted screening strategies are required that incorporate early, prevention focused testing and personalised risk stratification.
CholecTriplet2022: Show me a tool and tell me the triplet — An endoscopic vision challenge for surgical action triplet detection
Authors: Chinedu Innocent Nwoye, Tong Yu, Saurav Sharma, Aditya Murali, Deepak Alapatt, Armine Vardazaryan, Kun Yuan, Jonas Hajek, Wolfgang Reiter, Amine Yamlahi, Finn-Henri Smidt, Xiaoyang Zou, Guoyan Zheng, Bruno Oliveira, Helena R. Torres, Satoshi Kondo, Satoshi Kasai, Felix Holm, Ege Özsoy, Shuangchun Gui, Han Li, Sista Raviteja, Rachana Sathish, Pranav Poudel, Binod Bhattarai, Ziheng Wang, Guo Rui, Melanie Schellenberg, João L. Vilaça, Tobias Czempiel, Zhenkun Wang, Debdoot Sheet, Shrawan Kumar Thapa, Max Berniker, Patrick Godau, Pedro Morais, Sudarshan Regmi, Thuy Nuong Tran, Jaime Fonseca, Jan-Hinrich Nölke, Estevão Lima, Eduard Vazquez, Lena Maier-Hein, Nassir Navab, Pietro Mascagni, Barbara Seeliger, Cristians Gonzalez, Didier Mutter, Nicolas Padoy
Journal: Medical Image Analysis (2023)
A commentary on ‘Application and development of noninvasive biomarkers for colorectal cancer screening: a systematic review’
Authors: Jiankun Ren, Xinpu Miao
Journal: International Journal of Surgery (2023)

aNursing School, Hebi Polytechnic, Henan, 458030, China bDepartment of Gastroenterology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Hainan, 570311 Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online ■ ■ *Corresponding author. Address: Department of Gastroenterology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Hainan, 570311, China. E-mail address: [email protected] (X. Miao). This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/
Nivolumab and ipilimumab with concurrent stereotactic radiosurgery for intracranial metastases from non-small cell lung cancer: analysis of the safety cohort for non-randomized, open-label, phase I/II trial
Authors: Mehmet Altan, Yan Wang, Juhee Song, James Welsh, Chad Tang, Nandita Guha-Thakurta, George R Blumenschein, Brett W Carter, Jeffrey S Wefel, Amol J Ghia, Debra N Yeboa, Mary Frances McAleer, Caroline Chung, Kristina D Woodhouse, Susan L McGovern, Chenyang Wang, Betty Y S Kim, Jeffrey S Weinberg, Tina M Briere, Yasir Y Elamin, Xiuning Le, Tina Cascone, Marcelo V Negrao, Ferdinandos Skoulidis, Renata Ferrarotto, John V Heymach, Jing Li
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Up to 20% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), for which the current standard of care is radiation therapy with or without surgery. There are no prospective data on the safety of stereotactic radiosurgery (SRS) concurrent with immune checkpoint inhibitor therapy for BM. This is the safety cohort of the phase I/II investigator-initiated trial of SRS with nivolumab and ipilimumab for patients with BM from NSCLC. Patients and methods This single-institution study included patients with NSCLC with active BM amenable to SRS. Brain SRS and systemic therapy with nivolumab and ipilimumab were delivered concurrently (within 7 days). The endpoints were safety and 4-month intracranial progression-free survival (PFS). Results Thirteen patients were enrolled in the safety cohort, 10 of whom were evaluable for dose-limiting toxicities (DLTs). Median follow-up was 23 months (range 9.7–24.3 months). The median interval between systemic therapy and radiation therapy was 3 days. Only one patient had a DLT; hence, predefined stopping criteria were not met. In addition to the patient with DLT, three patients had treatment-related grade ≥3 adverse events, including elevated liver function tests, fatigue, nausea, adrenal insufficiency, and myocarditis. One patient had a confirmed influenza infection 7 months after initiation of protocol treatment (outside the DLT assessment window), leading to pneumonia and subsequent death from hemophagocytic lymphohistiocytosis. The estimated 4-month intracranial PFS rate was 70.7%. Conclusion Concurrent brain SRS with nivolumab/ipilimumab was safe for patients with active NSCLC BM. Preliminary analyses of treatment efficacy were encouraging for intracranial treatment response.
Comparing maximum diameter and volume when assessing the growth of small abdominal aortic aneurysms using longitudinal CTA data: cohort study
Authors: Robin Ristl, Johannes Klopf, Andreas Scheuba, Anna Sotir, Florian Wolf, Christoph M Domenig, Anders Wanhainen, Christoph Neumayer, Martin Posch, Christine Brostjan, Wolf Eilenberg
Journal: International Journal of Surgery (2023)

Monitoring of abdominal aortic aneurysms (AAAs) is currently based on serial measurements of maximum aortic diameter. Additional assessment of aneurysm volume has previously been proposed to possibly improve growth prediction and treatment decisions. To evaluate the use of supplementing volume measurements, the authors aimed to characterise the growth distribution of AAA volume and to compare the growth rates of the maximum diameter and volume at the patient level.Maximum diameter and volume were monitored every 6 months in 84 patients with small AAAs, with a total of 331 computed tomographic angiographies (with initial maximum diameters of 30-68 mm). A previously developed statistical growth model for AAAs was applied to assess the growth distribution of volume and to compare individual growth rates for volume and for maximum diameter.The median (25-75% quantile) expansion in volume was 13.4 (6.5-24.7) % per year. Cube root transformed volume and maximum diameter showed a closely linear association with a within-subject correlation of 0.77. At the surgery threshold maximum diameter of 55 mm, the median (25-75% quantile) volume was 132 (103-167) ml. In 39% of subjects, growth rates for volume and maximum diameter were equivalent, in 33% growth was faster in volume and in 27% growth was faster in maximum diameter.At the population level, volume and maximum diameter show a substantial association such that the average volume is approximately proportional to the average maximum diameter raised to a power of three. At the individual level, however, in the majority of patient's AAAs grow at different pace in different dimensions. Hence, closer monitoring of aneurysms with sub-critical diameter but suspicious morphology may benefit from complementing maximum diameter by volume or related measurements.
Development of a peptide drug restoring AMPK and adipose tissue functionality in cancer cachexia
Authors: Honglei Ji, Felix Englmaier, Pauline Morigny, Maude Giroud, Pamina Gräsle, Sebastian Brings, Julia Szendrödi, Mauricio Berriel Diaz, Oliver Plettenburg, Stephan Herzig, Maria Rohm
Journal: Molecular Therapy (2023)

Cancer cachexia is a severe systemic wasting disease that negatively affects quality of life and survival in patients with cancer. To date, treating cancer cachexia is still a major unmet clinical need. We recently discovered the destabilization of the AMPK complex in adipose tissue as a key event in cachexia-related adipose tissue dysfunction and developed an AAV-based approach to prevent AMPK degradation and prolong cachexia-free survival. Here, we show the development and optimization of a prototypic peptide, Pen-X-ACIP, where the AMPK stabilizing peptide ACIP is fused to the cell-penetrating peptide moiety penetratin via a propargylic glycine linker to enable late-stage functionalization using click chemistry. Pen-X-ACIP was efficiently taken up by adipocytes, inhibited lipolysis and restored AMPK signaling. Tissue uptake assays showed a favorable uptake profile into adipose tissue upon intraperitoneal injection. Systemic delivery of Pen-X-ACIP into tumor-bearing animals prevented the progression of cancer cachexia without affecting tumor growth, and preserved body weight and adipose tissue mass with no discernable side effects in other peripheral organs, thereby achieving proof-of-concept. As Pen-X-ACIP also exerted its anti-lipolytic activity in human adipocytes, it now provides a promising platform for further (pre)clinical development towards a novel, first-in-class approach against cancer cachexia.
LIGHT/TNFSF14 promotes CAR-T cell trafficking and cytotoxicity through reversing immunosuppressive tumor microenvironment
Authors: Na Zhang, Xiaohong Liu, Juliang Qin, Yue Sun, Hao Xiong, Boxu Lin, Kexin Liu, Binghe Tan, Chenglin Zhang, Chenshen Huang, Shancheng Ren, Mingyao Liu, Bing Du
Journal: Molecular Therapy (2023)
mRNA Technology Transfer Programme
Authors: Georgia Bisbas
Journal: The Lancet Microbe (2023)

On April 17–21, 2023, over 200 participants gathered in Cape Town (South Africa) for the first face-to-face meeting of the mRNA Technology Transfer Programme, presided by WHO Director-General Tedros Adhanom Ghebreyesus. The week also marked the inauguration of the mRNA technology hub facility at Afrigen Biologics and Vaccines (henceforth Afrigen; Cape Town, South Africa). The programme, launched in 2021 as a response to the global COVID-19 vaccine access inequality, is a collaboration between WHO, Medicines Patent Pool, and private and public partners from 15 low-income and middle-income countries (LMICs) in Africa, Asia, Europe, and South America.
A commentary on ‘Advances in artificial intelligence (AI) based diagnosis and treatment of liver diseases – correspondence’
Authors: Mohammad Abavisani, Farhad Dadgar, Farzaneh Peikfalak, Masoud Keikha
Journal: International Journal of Surgery (2023)

Abavisani, Mohammad; Dadgar, Farhad; Peikfalak, Farzaneh; Keikha, Masoud Author Information
A commentary on ‘Preoperative carbohydrate loading with individualized supplemental insulin in diabetic patients undergoing gastrointestinal surgery: a randomized trial’
Authors: Hanwen Cao, Ke Zhang, Mingfeng Cao, Xinhuan Zhang
Journal: International Journal of Surgery (2023)

aShandong First Medical University&Shandong Academy of Medical Science, Shandong, 271000, China bDepartment of Endocrinology, the Second Affiliated Hospital of Shandong First Medical University, Shandong, 271000, China Fund program: Higher Educational Science and Technology Program of Shandong Province (J17KA246) Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online ■ ■ *Corresponding author. Address:CHINA. E-mail address: [email protected] (X. Zhang). This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/
The challenges in the monitoring of infectious diseases after the earthquake in Türkiye in 2023
Authors: Önder Ergönül, Şiran Keske, Apolina Ksinzik, Mustafa Güldan, Laşin Özbek, Alpay Azap, Serap Şimşek-Yavuz, Füsun Can, Sibel Sakarya
Journal: The Lancet Infectious Diseases (2023)
Low-Dose Computed Tomography Screening in Relatives With a Family History of Lung Cancer
Authors: Chi-Liang Wang, Kuo-Hsuan Hsu, Ya-Hsuan Chang, Chao-Chi Ho, Chun-Ju Chiang, Kun-Chieh Chen, Yun-Chung Cheung, Pei-Ching Huang, Yu-Ruei Chen, Chih-Yi Chen, Chung-Ping Hsu, Jiun-Yi Hsia, Hsuan-Yu Chen, Shi-Yi Yang, Yao-Jen Li, Tsung-Ying Yang, Jeng-Sen Tseng, Cheng-Yen Chuang, Chao A. Hsiung, Yuh-Min Chen, Ming-Shyan Huang, Chong-Jen Yu, Kuan-Yu Chen, Wu-Chou Su, Jeremy J.W. Chen, Sung-Liang Yu, Chien-Jen Chen, Pan-Chyr Yang, Ying-Huang Tsai, Gee-Chen Chang
Journal: Journal of Thoracic Oncology (2023)

BACKGROUND The role of family history of lung cancer (LCFH) in screening using low-dose computed tomography (LDCT) has not been prospectively investigated and with long-term follow-up. METHODS A multicenter prospective study with up to three rounds of annual LDCT screening was conducted to determine the detection rate of LC in asymptomatic first or second-degree relatives of LCFH. RESULTS From 2007 to 2011, there were 1,102 participants enrolled, including 805 and 297 from simplex (SF) and multiplex families (MF), respectively (54.2% female, and 70.0% never-smokers). Last follow-up date was May 05, 2021. The overall LC detection rate was 4.5% (50/1102). The detection rate in MF was 9.4% (19/202) and 4.4% (4/91) in never-smokers and who smoked, respectively. The corresponding rates for SF were 3.7% (21/569) and 2.7% (6/223), respectively. Of them, 68.0% and 22.0% of cases with stage I and IV diseases, respectively. LC diagnoses within a 3-year interval from initial screening were younger, higher detection rate, and more stage I disease; thereafter, more stage III/IV disease and 66.7% (16/24) with negative or semi-positive nodules in initial CT scans. Within the 6-year interval, only maternal (modified rate ratio [RR]=4.46, 95% confidence interval [CI]=2.32–8.56) or maternal relative history of LC (modified RR=5.41, 95% CI=2.84–10.30) increased the risk of LC. CONCLUSION LCFH is a risk factor for LC, more in MF history, never-smokers, younger adults, and those with maternal relatives with LC. Randomized controlled trials are needed to confirm mortality benefit of LDCT screening in those with LCFH.
Autologous blood transfusion reduces the requirement for perioperative allogenic blood transfusion in patients undergoing major hepatopancreatobiliary surgery: a retrospective cohort study
Authors: Adil S Lakha, Radhika Chadha, Stephen Von-Kier, Antonio Barbosa, Keith Maher, Martin Pirkl, Mark Stoneham, Michael A Silva, Zahir Soonawalla, Venkatesha Udupa, Srikanth Reddy, Alex Gordon-Weeks
Journal: International Journal of Surgery (2023)

Introduction: Major hepatopancreatobiliary surgery is associated with a risk of major blood loss. We aimed to assess whether autologous transfusion of blood salvaged intra-operatively reduces the requirement for post-operative allogenic transfusion in this patient cohort. Materials and methods: In this single centre study, information from a prospective database of 501 patients undergoing major HPB resection (2015–2022) was analysed. Patients who received cell salvage (n=264) were compared with those who did not (n=237). Non-autologous (allogenic) transfusion was assessed from the time of surgery to 5 days post-surgery, and blood loss tolerance was calculated using the Lemmens-Bernstein-Brodosky formula. Multivariate analysis was used to identify factors associated with allogenic blood transfusion avoidance. Results: 32% of lost blood volume was replaced through autologous transfusion in patients receiving cell salvage. Although the cell salvage group experienced significantly higher intra-operative blood loss compared with the non-cell salvage group (1360 ml vs 971 ml, P =0.0005), they received significantly less allogenic red blood cell units (1.5 vs. 0.92 units/patient, P =0.03). Correction of blood loss tolerance in patients who underwent cell salvage was independently associated with avoidance of allogenic transfusion (OR 0.05 (0.006–0.38) P =0.005). In a subgroup analysis, cell salvage use was associated with a significant reduction in 30-day mortality in patients undergoing major hepatectomy (6% vs. 1%, P =0.04). Conclusion: Cell salvage use was associated with a reduction in allogenic blood transfusion and a reduction in 30-day mortality in patients undergoing major hepatectomy. Prospective trials are warranted to understand whether the use of cell salvage should be routinely utilised for major hepatectomy.